Peripheral B Cell Receptor Editing

这项建议详细说明了一项为期5年的培训计划，该计划旨在发展B细胞发育生物学和免疫耐受研究的学术生涯。PI已经加入了Fred Alt的实验室，研究B细胞受体编辑和免疫球蛋白轻链重排的调节，并计划利用Alt严格的科学环境来开发尖端分子工具方面的专业知识。当他成为一名独立的调查员时，PI计划随后利用这些工具来剖析B细胞免疫学中临床相关问题的机制和分子基础。该协会目前是临床医学研究员，在弗雷德里克·阿尔特博士(导师)和弗兰克·奥斯汀博士(共同导师)的指导下进行研究。他的研究重点涉及他最近发现的一种B细胞亚群的特征，该亚群可以重排肠系膜淋巴B细胞中的免疫球蛋白轻链(Ig())基因。在拟议的计划中，PI将描述这群外周编辑细胞的特征(目标1)，并开发小鼠模型来研究这种Ig(与肠道环境的免疫耐受性有关的基因重排活动)(目标2)。在目标3中，他将继续进行研究，以阐明免疫球蛋白轻链基因重排调节的分子机制。总之，这一建议的结果将促进我们对B细胞发育、抗体特异性调节以及V(D)J重排机制对DNA可及性的调节机制的理解。此外，这些研究可能有助于理解外周B细胞受体在过敏和/或炎症性疾病过程中的编辑。这位导师是该领域的一位杰出的科学家，有100多名既定的受训人员，他完全专注于他目前的实验室计划。这位共同导师也是一位在过敏性疾病小鼠模型方面拥有专业知识的著名科学家，他将帮助候选人的职业发展。咨询委员会成员是非常杰出、受人尊敬的免疫学家，他们还将监督这项提案的进展，并在预定的会议和非正式会议上对方法和结果的解释提出批评。这项研究将在波士顿儿童医院免疫疾病研究所/细胞和分子医学项目的高度合作环境中进行。PI还将受益于他的家乡机构--BWH的炎症和过敏性疾病研究科的环境。这两个机构都致力于提供必要的资源和培训，以帮助主要调查员建立独立的职业生涯。我们的免疫系统不能产生耐受的食物和“好”细菌会导致疾病。研究确定对这些物质的耐受机制对于设计预防和治疗食物过敏和炎症性肠病的新疗法至关重要。

This proposal details a 5 year training program for the development of an academic career in the study of B cell developmental biology and immune tolerance. The PI has joined the laboratory of Fred Alt to study B cell receptor editing and the regulation of immunoglobulin light chain rearrangement, and plans to utilize the rigorous scientific environment in the Alt to develop expertise in cutting edge molecular tools. The PI plans to then utilize these tools as he becomes an independent investigator to dissect the mechanistic and molecular underpinnings of clinically relevant problems in B cell immunology. The PI is currently a Clinical Fellow in Medicine conducting research under the direction of Dr. Frederick Alt (mentor) and Dr. Frank Austen (co-mentor). His research focus involves the characterization of a subpopulation of B cells that he recently found to rearrange the immunoglobulin lambda light chain (Ig() locus in mesenteric lymph node B cells. In the proposed plan, the PI will characterize this population of peripheral editing cells (Aim 1) and develop mouse models to investigate this Ig( locus rearrangement activity with respect to immunological tolerance to the gut environment (Aim 2). In Aim 3, he will pursue studies to elucidate the molecular mechanisms involved in regulation of immunoglobulin light chain gene rearrangements. Together, results from this proposal will advance our understanding of the mechanisms of B cell development, antibody specificity modulation and regulation of DNA accessibility to V(D)J rearrangement machinery. Moreover, these studies may aid the understanding of peripheral B cell receptor editing in allergic and/or inflammatory disease processes. The mentor is an eminent scientist in the field with over 100 established trainees and is fully focused on his current laboratory program. The co-mentor is also an eminent scientist with expertise in mouse models of hypersensitivity diseases who will aid in the candidates career development. Advisory committee members are exceptionally outstanding, respected immunologists who will also oversee the progress of this proposal and provide critique on the methods and interpretation of results at scheduled meetings and informally. The research will take place within the highly collaborative environment of the Immune Disease Institute/Program for Cellular and Molecular Medicine at the Children's Hospital Boston. The PI will also benefit from the environment of his home institution, the Inflammation and Allergic Diseases Research Section at BWH. Both of these institutions are committed to providing the necessary resources and training to help the primary investigator establish an independent career. Failure of our immune system to develop tolerance food and "good" bacteria leads to disease. Studies to determine the mechanism of tolerance to these entities will be critical to designing new therapies for prevention and treatment of food allergy and inflammatory bowel disease.